Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

Damini Jawaheer; Wentian Li; Robert R. Graham; Wei Chen; Aarti Damle; Xiangli Xiao; Joanita Monteiro; Houman Khalili; Annette Lee; Robert Lundsten; Ann Begovich; Teodorica Bugawan; Henry Erlich; James T. Elder; Lindsey A. Criswell; Michael F. Seldin; Christopher I. Amos; Timothy W. Behrens; Peter K. Gregersen

doi:10.1086/342407

Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

Damini Jawaheer, Wentian Li, Robert R. Graham, Wei Chen, Aarti Damle, Xiangli Xiao, Joanita Monteiro, Houman Khalili, Annette Lee, Robert Lundsten, Ann Begovich, Teodorica Bugawan, Henry Erlich, James T. Elder, Lindsey A. Criswell, Michael F. Seldin, Christopher I. Amos, Timothy W. Behrens, Peter K. Gregersen

Medicine, Rheumatology Division

Research output: Contribution to journal › Article › peer-review

162 Scopus citations

Abstract

Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

Original language	English (US)
Pages (from-to)	585-594
Number of pages	10
Journal	American journal of human genetics
Volume	71
Issue number	3
DOIs	https://doi.org/10.1086/342407
State	Published - 2002

Funding

This work was supported by National Institutes of Health grants R01-AR44222 and N01-AR7-2232 (to P.K.G.) and R01-AR43274 and P01-AR45231-SCOR in SLE (to T.W.B.). These studies were performed, in part, in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by National Center for Research Resources grant 5-M01-RR-00079. The NARAC includes a subset of the authors (P.K.G., L.A.C., M.F.S., and C.I.A.), as well as the following individuals: Salvatore Albani (University of California, San Diego), S. Louis Bridges (University of Alabama at Birmingham), Leigh F. Callahan (University of North Carolina), Daniel O. Clegg (University of Utah), Donald Flemming (Bethesda Naval Medical Center), Daniel L. Kastner (National Institute of Arthritis and Musculoskeletal and Skin Diseases), Marlene Kern (North Shore–Long Island Jewish Research Institute), J. Lee Nelson (Fred Hutchinson Cancer Research Center), Theodore Pincus (Vanderbilt University), David S. Pisetsky (Duke University), Richard Pope (Northwestern University), Harry W. Schroeder (University of Alabama at Birmingham), Ryk Ward (Oxford University), and Mark H. Wener (University of Washington). Support for the NARAC is provided, in part, by the National Arthritis Foundation. Finally, we wish to thank the patients and families who made these studies possible through their generous participation.

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1086/342407

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Jawaheer, D., Li, W., Graham, R. R., Chen, W., Damle, A., Xiao, X., Monteiro, J., Khalili, H., Lee, A., Lundsten, R., Begovich, A., Bugawan, T., Erlich, H., Elder, J. T., Criswell, L. A., Seldin, M. F., Amos, C. I., Behrens, T. W., & Gregersen, P. K. (2002). Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. American journal of human genetics, 71(3), 585-594. https://doi.org/10.1086/342407

@article{b37697b7bae54ba3bfd1ea0af58283ea,

title = "Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis",

abstract = "Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 {"}shared epitope{"} in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.",

author = "Damini Jawaheer and Wentian Li and Graham, {Robert R.} and Wei Chen and Aarti Damle and Xiangli Xiao and Joanita Monteiro and Houman Khalili and Annette Lee and Robert Lundsten and Ann Begovich and Teodorica Bugawan and Henry Erlich and Elder, {James T.} and Criswell, {Lindsey A.} and Seldin, {Michael F.} and Amos, {Christopher I.} and Behrens, {Timothy W.} and Gregersen, {Peter K.}",

note = "Funding Information: This work was supported by National Institutes of Health grants R01-AR44222 and N01-AR7-2232 (to P.K.G.) and R01-AR43274 and P01-AR45231-SCOR in SLE (to T.W.B.). These studies were performed, in part, in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by National Center for Research Resources grant 5-M01-RR-00079. The NARAC includes a subset of the authors (P.K.G., L.A.C., M.F.S., and C.I.A.), as well as the following individuals: Salvatore Albani (University of California, San Diego), S. Louis Bridges (University of Alabama at Birmingham), Leigh F. Callahan (University of North Carolina), Daniel O. Clegg (University of Utah), Donald Flemming (Bethesda Naval Medical Center), Daniel L. Kastner (National Institute of Arthritis and Musculoskeletal and Skin Diseases), Marlene Kern (North Shore–Long Island Jewish Research Institute), J. Lee Nelson (Fred Hutchinson Cancer Research Center), Theodore Pincus (Vanderbilt University), David S. Pisetsky (Duke University), Richard Pope (Northwestern University), Harry W. Schroeder (University of Alabama at Birmingham), Ryk Ward (Oxford University), and Mark H. Wener (University of Washington). Support for the NARAC is provided, in part, by the National Arthritis Foundation. Finally, we wish to thank the patients and families who made these studies possible through their generous participation. ",

year = "2002",

doi = "10.1086/342407",

language = "English (US)",

volume = "71",

pages = "585--594",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

Jawaheer, D, Li, W, Graham, RR, Chen, W, Damle, A, Xiao, X, Monteiro, J, Khalili, H, Lee, A, Lundsten, R, Begovich, A, Bugawan, T, Erlich, H, Elder, JT, Criswell, LA, Seldin, MF, Amos, CI, Behrens, TW & Gregersen, PK 2002, 'Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis', American journal of human genetics, vol. 71, no. 3, pp. 585-594. https://doi.org/10.1086/342407

TY - JOUR

T1 - Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

AU - Jawaheer, Damini

AU - Li, Wentian

AU - Graham, Robert R.

AU - Chen, Wei

AU - Damle, Aarti

AU - Xiao, Xiangli

AU - Monteiro, Joanita

AU - Khalili, Houman

AU - Lee, Annette

AU - Lundsten, Robert

AU - Begovich, Ann

AU - Bugawan, Teodorica

AU - Erlich, Henry

AU - Elder, James T.

AU - Criswell, Lindsey A.

AU - Seldin, Michael F.

AU - Amos, Christopher I.

AU - Behrens, Timothy W.

AU - Gregersen, Peter K.

N1 - Funding Information: This work was supported by National Institutes of Health grants R01-AR44222 and N01-AR7-2232 (to P.K.G.) and R01-AR43274 and P01-AR45231-SCOR in SLE (to T.W.B.). These studies were performed, in part, in the General Clinical Research Center, Moffitt Hospital, University of California, San Francisco, with funds provided by National Center for Research Resources grant 5-M01-RR-00079. The NARAC includes a subset of the authors (P.K.G., L.A.C., M.F.S., and C.I.A.), as well as the following individuals: Salvatore Albani (University of California, San Diego), S. Louis Bridges (University of Alabama at Birmingham), Leigh F. Callahan (University of North Carolina), Daniel O. Clegg (University of Utah), Donald Flemming (Bethesda Naval Medical Center), Daniel L. Kastner (National Institute of Arthritis and Musculoskeletal and Skin Diseases), Marlene Kern (North Shore–Long Island Jewish Research Institute), J. Lee Nelson (Fred Hutchinson Cancer Research Center), Theodore Pincus (Vanderbilt University), David S. Pisetsky (Duke University), Richard Pope (Northwestern University), Harry W. Schroeder (University of Alabama at Birmingham), Ryk Ward (Oxford University), and Mark H. Wener (University of Washington). Support for the NARAC is provided, in part, by the National Arthritis Foundation. Finally, we wish to thank the patients and families who made these studies possible through their generous participation.

PY - 2002

Y1 - 2002

N2 - Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

AB - Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.

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SN - 0002-9297

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JO - American journal of human genetics

JF - American journal of human genetics

IS - 3

ER -

Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis

Abstract

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ASJC Scopus subject areas

UN SDGs

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